ANZCTR - Registration

Registration number

ACTRN12616001524482

Ethics application status

Approved

Date submitted

6/09/2016

Date registered

4/11/2016

Date last updated

3/10/2018

Type of registration

Retrospectively registered

Titles & IDs

Public title

EWING 2008 Clinical trial for the treatment of Localized and Disseminated Ewing sarcoma

Scientific title

EWING 2008 is a phase 3, open label, multi-centre, randomised controlled trial of international study groups with the intention of optimising treatment and treatment results in patients with localised and advanced Ewing sarcomas.

Secondary ID [1]

None

Universal Trial Number (UTN)

Trial acronym

EE08

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Ewing Sarcoma of bone or soft tissue.

Condition category

Condition code

Cancer

Sarcoma (also see 'Bone') - soft tissue

Cancer

Bone

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

All patient receive induction chemotherapy- six cycles of VIDE (Jurgens, 2006). Disease assessment will be performed prior to treatment and after the 2nd (latest 3rd) and 5th (latest 6th) cycle of VIDE chemotherapy.The decision regarding local therapy must be made following the fifth cycle of of induction treatment, with preference for surgical intervention with or without additional radiotherapy.Depending on the presentation at the time of diagnosis and on the histological response to induction chemotherapy, patients will be stratified into to the following risk groups:
Standard Risk R1: (1) Patients with localised disease and good histological response at surgery after induction chemotherapy and (2) Patients with initial surgery or in whom surgery was not feasible and who have small tumours < 200 mL at diagnosis.
High Risk localised disease R2loc*: (1) Patients with localised disease and poor histological response at surgery after induction chemotherapy and (2) Patients with initial surgery or in whom surgery was not feasible and who have large tumours > 200 mL at diagnosis.High Risk primary lung metastases R2pulm*: Patients with a Ewing sarcoma metastatic to the lungs and/or pleura, but not to any other sites, at the time of diagnosis.
Very High Risk R3: Patients with metastatic disease not confined to the lungs and/or pleura, i.e. patients with bone metastases, bone marrow metastases or other metastases (e.g. lymph nodes, liver, CNS, etc) with and without additional pulmonary metastases at the time of diagnosis.

Good responders (R1) will receive an additional eight cycles of chemotherapy VAC (Female) or VAI (Male). They will be randomised to receive add-on treatment with zoledronic acid, or no add-on treatment. High Risk R2 *Poor responders (R2) with localised disease (R2loc) and primary pulmonary metastases (R2pulm) will continue to be randomised as in EURO-E.W.I.N.G. 99 to receive either eight cycles of VAI chemotherapy or high dose treatment with busulfan-melphalan. Very High Risk (R3) patients receive six cycles of VIDE induction chemotherapy and are then randomised to either continue with eight cycles of VAC chemotherapy or high dose treosulfan-melphalan (TreoMel) chemotherapy followed by autologous stem cell reinfusion, followed thereafter by eight cycles of VAC chemotherapy.

##Treosulfan IV 12 g/m^2/dose IV infusion, d-5 to d-3.
##Melphalan IV 140 mg/m^2 IV infusion,.
## Busulfan IV, day -6 to d -3 adults: 0.8 mg/kg body weight (BW) children and adolescents: <9 kg= 1mg/kg BW 9 - <16 kg= 1.2 mg/kg BW 16 - 23 kg= 1.1 mg/kg BW >23 - 34 kg= 0.95 mg/kg BW >34 kg = 0.8 mg/kg BW
##Stem cell re-infusion (min. 3 x 106/kg CD 34+)
##Zoledronic acid IV at 28 day intervals beginning with cycle 6 of VAC/VAI consolidation chemotherapy for a total period of 9 months. Pts < 18 years will receive 0.05 mg/kg BW by IV infusion 30 min-1 h. Pts >= 18 years will receive a bodyweight-dependent dose: Patients >40kg receive 4 mg by IV infusion 30 min-1h Patients 20-40 kg receive 2 mg by IV infusion 30 min-1h
**Basic plan of zoledronic acid**
Cycles should be given at 28-D intervals for a maximum of 9 cycles beginning with cycle 6 of VAC/VAI consolidation chemotherapy (cycle 12 from start of chemotherapy). Paralell to
cycles, the medication may be given at 21-d intervals. Following completion of consolidation chemotherapy, the interval must be extended to the 28-d schedule.
D 1
Zoledronic acid, hydration 250 mL/m2
Ds 2-6
Oral calcium , paracetamol in case of flu-like symptoms
D 7 and Prior to next cycle
Controls according to institutional guidelines

***Basic plan of TreoMel**
Ds -5 to -3 Treosulfan, Hydration
D -2 Melphalan, Hydration
D -1 Hydration
D 0 Stem cell reinfusion, Hydration
D +5 until recovery
Hydration
Recommended:
G-CSF 5 microg/kg/d d5 to approx. d13
or PEG-G-CSF according to manufacturer’s guidance.
Regular controls according to institutional guidelines
All blood products must be irradiated and leukocyte-depleted.

***VIDE**
VINCRISTINE 1.5 mg/m2/d d1 (1.5 mg/m2/cycle) (max. single dose: 2 mg)
(i.v. push)
IFOSFAMIDE 3.0 g/m2/d d1, d2, d3 (9 g/m2/cycle) plus MESNA*
(i.v. infusion, 1-3 h)
DOXORUBICIN 20 mg/m2/d d1, d2, d3 (60 mg/m2/cycle)
(i.v. infusion, 4 h)
ETOPOSIDE 150 mg/m2/d d1, d2, d3 (450 mg/m2/cycle)
(i.v. infusion, 1 h)
G-CSF 5 microg/kg/d d5 to approx. d13
*Recommended Mesna dosage:
1.0 g/m2/d d1 (i.v. push 1 h prior to ifosfamide)
3.0 g/m2/d d1, d2, d3 (i.v. infusion, e.g. 24 h)

Cycles of VIDE should be given at 21-d intervals or on haematological recovery to WBC >= 2.0*109/L with absolute neutrophil count (ANC) >= 1.0*109/L; platelets >= 80*109/L.

##Basic plan of VIDE cycles ##

D 1 Vincristine, Ifosfamide, Doxorubicin, Etoposide, Mesna bolus, Mesna, Hydration
D 2 Ifosfamide, Doxorubicin, Etoposide, Mesna, Hydration
D 3 Ifosfamide, Doxorubicin, Etoposide, Mesna, Hydration
D 4 Hydration
D 5 G-CSF until leukocyte recovery Ds 5 – 19
Regular follow-up visits as needed. FBC controls according to institutional guidelines. Ds 20-22 PRIOR TO NEXT CYCLE Controls according to institutional guidelines including
FBC, urea & electrolytes, calcium, magnesium, phosphate, bicarbonate, alkaline phosphatase, bilirubin, liver enzymes
GFR (calculated creatinine clearance (Ccrea) or isotopic)
Fractional phosphate reabsorption (Tp/Ccrea) = Renal tubular threshold for phosphate (Tmp/GFR).
Cardiac monitoring

***VAI**
VINCRISTINE IV, 1.5 mg/m2/d d1 (1.5 mg/m2/cycle) (max. single dose: 2 mg)
ACTINOMYCIN IV, D 0.75 mg/m2/d d1, d2 (1.5 mg/m2/cycle) (max. single dose per d: 1.5 mg)
IFOSFAMIDE IV, 3.0 g/m2/d d1, d2 (6 g/m2/cycle) plus MESNA*
G-CSF 5microg/kg/d in case of poor haematological recovery
*Recommended Mesna dosage
IV, 1.0 g/m2/d d1 (i.v. push 1 h prior to ifosfamide)
IV, 3.0 g/m2/d d1, d2

Cycles of VAI should be given at 21-d intervals or on haematological recovery to WBC >= 2.0*109/L with absolute neutrophil count (ANC) >= 1.0*109/L; platelets >= 80*109/L.

## Basic plan of VAI##
D 1 Vincristine, Actinomycin D, Ifosfamide, Mesna bolus, Mesna, Hydration
D 2 Actinomycin D, Ifosfamide, Mesna, Hydration
D 3 Hydration
Ds 4-9 Controls as needed according to institutional guidelines
D 5 G-CSF 5microg/kg/d in patients with history of poor haematological recovery Ds 10-19
Regular check-up visits, FBC controls according to institutional guidelines Ds 20-22 PRIOR TO NEXT CYCLE Controls according to institutional guidelines including
- FBC
- Urea & electrolytes, calcium, magnesium, phosphate, bicarbonate, alkaline phosphatase, bilirubin, liver enzymes
- GFR (calculated creatinine clearance (Ccrea) or isotopic)
- Fractional phosphate reabsorption (Tp/Ccrea) = Renal tubular threshold for phosphate (Tmp/GFR).

***VAC**
VINCRISTINE IV, 1.5 mg/m2/d d1 (1.5mg/m2/cycle) (max. single dose: 2 mg)
ACTINOMYCIN D IV, 0.75 mg/m2/d d1, d2 (1.5mg/m2/cycle) (max. single dose/d: 1.5 mg)
CYCLOPHOSPHAMIDE IV, 1500mg/m2/d d1 (1500 mg/m2/cycle) plus MESNA*
*Recommended Mesna dosage
500 mg/m2/d d1 (i.v. push 1 h prior to cyclophosphamide)
1500 mg/m2/d d1 (i.v. infusion, e.g. 24 h)
Cycles of VAC should be given at 21-d intervals or on haematological recovery to WBC => 2.0*109/L with absolute neutrophil count (ANC) => 1.0*109/L; platelets => 80*109/L.

##Basic plan of VAC##
D 1 Vincristine, Actinomycin D, Cyclophosphamide, Mesna bolus, Mesna, Hydration
D 2 Actinomycin D
D 3-9 Controls as needed according to institutional guidelines
D 5 G-CSF 5microg/kg/d in patients with history of poor haematological recovery
Ds 10-19 FBC controls according to institutional guidelines.

Busulfan–Melphalan Patients randomised* to BuMel receive busulfan-melphalan consolidation as cycle 8.
As only the IV formulation of busulfan (Busilvex TM) has obtained approval for use in high-dose treatment regimens it is recommended for use within this trial.
* R2 accrual discontinued on December 1st 2015

Bu (Busulfan)
Adults: 0.8 mg/kg
Children and adolescents:
<9 kg = 1 mg/kg
9-<16 kg = 1.2 mg/kg
16-23 kg = 1.1 mg/kg
>23-34 kg= 0.95 mg/kg
>34 kg = 0.8 mg/kg

Melphalan (Mel) 140 mg/m²

Basic plan of BuMel
Day -7 Clonazepam, Hydration
Day -6 to -3 Clonazepam, Busulfan, Hydration
Day -2 Clonazepam, Melphalan, Hydration
Day -1 Clonazepam, Hydration
Day 0 Stem cell reinfusion, Hydration
Day +5 until recovery Hydration
Recommended:
G-CSF 5 microg/kg/d d5 to approx. d13
or PEG-G-CSF according to manufacturer’s guidance.

Intervention code [1]

Treatment: Drugs

Intervention code [2]

Treatment: Other

Comparator / control treatment

All patient receive induction chemotherapy- six cycles of VIDE. The decision regarding local therapy must be made following the fifth cycle of of induction treatment, with preference for surgical intervention with or without additional radiotherapy.

Good responders (R1) are allocated to standard risk arm and will receive an additional eight cycles of chemotherapy VAC (Female) or VAI (Male). Patients are randomised to add-on treatment with zoledronic acid in addition to induction and maintenance chemotherapy compared to no add-on treatment.

High Risk localised disease R2loc: (1) Patients with localised disease and poor histological response at surgery after induction chemotherapy and (2) Patients with initial surgery or in whom surgery was not feasible and who have large tumours > 200 mL at diagnosis.
High Risk primary lung metastases R2pulm: Patients with a Ewing sarcoma metastatic to the lungs and/or pleura, but not to any other sites, at the time of diagnosis.
pts were randomised to high-dose chemotherapy using busulfan-melphalan with autologous stem cell reinfusion, compared with standard chemotherapy,
*****High Risk R2loc patients (who are poor responders with localised disease or patients with large tumour volumes non eligible of assessment of histological response) will be reclassified as registry patients as of December 1st 2015.

******High risk R2pulm patients are to be classified as registry patients after December 1st 2015.

Very High Risk (R3) patients receive six cycles of VIDE induction chemotherapy and the control arm continue with eight cycles of vAC chemotherapy.
Patients are randomised to high dose chemotherapy using treosulfan-melphalan followed by autologous stem cell reinfusion to eight cycles of standard adjuvant chemotherapy, compared to eight cycles of standard adjuvant chemotherapy alone,

Control group

Active

Outcomes

Primary outcome [1]

Event free survival in Standard risk (R1): to examine whether additional maintenance treatment with zoledronic acid, compared to no no add-on treatment, improves event-free survival in patients with localised disease and favourable risk profile.

Value of PET / PET-CT
PET analyses will be performed at initial diagnosis and after the 2nd (or 3rd)) and 5th (or 6th) cycle of VIDE. The value for diagnosis and response evaluation will be assessed in comparison with standard imaging procedures such as MRI, CT scan, 99TC scintigraphy. For response evaluation, histological response will serve as an additional parameter to be compared. As FDG-PET and PET-CT may not be available in all participating institutions, PET is not mandatory and the lack of a PET investigation does not violate any of the basic codes of practice defined within the treatment protocol.

Timepoint [1]

Event-free survival time (EFS) starts at the date of randomisation and ends at the date of first event (progression of disease, relapse of disease, diagnosis of secondary malignancy, or death of the patient irrespective of its cause) or at the date of the patient's most recent consultation.
Time Frame: 9.5 years

Primary outcome [2]

Event free survival in High Risk (R2) In a randomised trial, to examine whether the introduction of busulfan-containing high-dose chemotherapy followed by autologous stem cell reinfusion, in comparision with a standard chemotherapy, is of benefit in patients with poor histological response of localised disease or who have pulmonary/pleural metastases. (Note: R2 accrual disscontinued on Dec 1 2015)

The outcome is assessed with Value of PET / PET-CT

Timepoint [2]

Event-free survival time (EFS) starts at the date of randomisation and ends at the date of first event (progression of disease, relapse of disease, diagnosis of secondary malignancy, or death of the patient irrespective of its cause) or at the date of the patient's most recent consultation.
Time of first event is defined as follows:
Event: Date of occurrence
Progression*: Date of diagnosis of progression
Relapse*: Date of diagnosis of relapse
Secondary malignancy: Date of diagnosis of secondary malignancy
Death, whatever cause: Date of death
*Progression of disease is defined as recurrent disease under active oncological therapy. Relapse of disease is defined as recurrent disease in patients with complete clinical remission after completion of active oncological therapy.
Time Frame: 9.5 years

Primary outcome [3]

Event free survival in Very High Risk (R3): In a randomised trial to examine whether after VIDE induction chemotherapy, the additionof high-dose treosulfan-melphalan chemotherapy, followed by autologous stem cell reinfusion, to eight cycles of VAC chemotherapy, compared to eight cycles of standards adjuvant chemotherapy alone, improves event-free survival in patients with primary disseminated disease.

The outcome is assessed with Value of PET / PET-CT

Timepoint [3]

Event-free survival time (EFS) starts at the date of randomisation and ends at the date of first event (progression of disease, relapse of disease, diagnosis of secondary malignancy, or death of the patient irrespective of its cause) or at the date of the patient's most recent consultation.

Time Frame: 9.5 years

: The primary endpoint of event-free survival (EFS) will be estimated according to the method of Kaplan and Meier (Kaplan&Meier 1958).

Secondary outcome [1]

Overall survival: to investigate whether add-on treatment in R1, busulfan high-dose treatment in R2 and the addition of treosulfan high-dose treatment in R3 lead to an improvement in overall survival.

Timepoint [1]

Overall survival :Time Frame: 9.5 years

Overall survival time (OS) starts at the date of randomisation and ends at the date of death of the patient (irrespective of its cause) or at the date of the patient's most recent consultation. Patients lost to follow-up are censored at the date of their last consultation.

Secondary outcome [2]

Toxicity: To investigate the short-term and long-term toxicity in all patients.

The acceptability of the safety profile of chemotherapy and radiotherapy administered throughout this trial will be assessed by the incidence of toxicities (adverse reactions) as recorded by checklist and the incidence of reported unanticipated serious adverse events throughout the trial and in the follow-up period to include late toxicities.
Unanticipated SAEs will be reported on an SAE Form. Other, anticipated AEs (toxicities), both serious and non-serious, will be recorded by checklist.

expected AEs:
Neutropenia and neutropenic fever (CTCAE 1-4).
Haematological toxicity: haemoglobin, WBC, granulocytes, platelets (CTCAE 1-4 ). Infections and fever (CTCAE 1-3).
Gut toxicity (mucositis / stomatitis, vomiting, diarrhoea) (CTCAE 1-3).
Other expected AEs CTCAE 1-3.

Timepoint [2]

Until 3 months after completion of protocol defined therapy
Safety and toxicity :Time Frame: permanent

Secondary outcome [3]

Quality of Life:
Participation in the QoL assessment is optional as explained in the patient information sheet and informed consent form.
QoL is assessed in patients aged 18 and over using the EORTC-QLQ-C30 questionnaire (Aaronson, 1993, Fayers, 1995) and in patients aged 17 and under by the PedsQL questionnaire (Varni, 2002).

Timepoint [3]

After 5-6 cycles of induction chemotherapy
Quality of life : Time Frame: 9.5 years
QoL will be assessed in R1 and R3 patients four times during protocol treatment:
- after completion of the first VIDE cycle and prior to starting the 2nd cycle of induction chemotherapy, - within two weeks after completion of induction chemotherapy and before surgery or irradiation, - after completion of the protocol therapy, - two years after completion of the protocol therapy.

Secondary outcome [4]

Impact of the time to diagnosis on presentation and outcome is a composite secondary outcome : To investigate the impact of the time to diagnosis on the presentation and outcome of the patients. The impact of the time to diagnosis will be assessed by review of medical records and MRI/PET scans results when the last patient enrolled in the study has finished treatment.

Due to the inconspicuousness of the early warning signs the diagnosis of Ewing sarcoma is often delayed. As yet, the average time of delay and the putative consequences of a delayed diagnosis have not been investigated. Therefore, we aim to investigate the impact of the time to diagnosis on presentation of disease and outcome.

Timepoint [4]

The impact of the time to diagnosis will be assessed when the last patient enrolled in the study has finished treatment.

Eligibility

Key inclusion criteria

Histologically confirmed Ewing sarcoma of bone or soft tissue.
Age > 48 months and <50 years at the date of diagnostic biopsy.
Registration must be < 45 days from diagnostic biopsy/surgery.
Start of chemotherapy < 45 days from diagnostic biopsy/surgery.
Informed consent must be signed prior to study entry.
Performance status: Lansky or Karnofsky score >50%, may be modified for handicapped patients.
Haematological parameters: Hb > 8 g/dl (transfusion allowed); Platelets > 80.000 /ul (transfusion allowed); WBC > 2000/ul.
Cardiac: LVEF > 40%; SF > 28%

Minimum age

48 Months

Maximum age

50 Years

Sex

Both males and females

Can healthy volunteers participate?

No

Key exclusion criteria

More than one cycle of chemotherapy prior to registraion.
Secondary malignancy.
Pregnant or lactation.
Concurrent treatment within any other clinical trial, except trials with different endpoints that due t the nature of their endpoints must run parallel to EWING 2008, eg trials on antiemetics, antimycotics, stategies for psychosocial support, etc.
Any other medical, psychiatric, or social condition incompatible with the protocol treamtent.

Study design

Statistical methods / analysis

Survival anaylsis: All patients randomised in the trial will be included in the intent-to-treat analysis in their allocated treatment group. For certain questions additional 'per protocol' analysis are intended. No patient will be excluded from analysis once he or she is entered into the study, unless informed consent is withdrawn. Event-free survival and overall survival will be estimated according to the method of Kaplan and Meier (1958(.
Comparison between randomised arms and analysis of prognostic factors: Comparisions are performed by logrank tests. Variables are univariately analysed regarding impact on EFS by logrank test or chi-square analysis as appropriate. Multivariate analyses of variables with regard to EFS times are performed by Cox analysis (1972). Analyses of specific failure risks are performed by means of competing risk analysis (1995). Those patients who are included in the study but cannot be randomised will be included in exploratory analyses for EFS and OS outcomes.

****NUMBER OF SUBJECTS 633 (R1+R3) plus patients recruited in R2loc and R2pulm by the predetermined end of recruitment

****Sample Size****

All power calculations in R1 and R3 were based on 3-year EFS rates performing a two–sided (except R3: one side-hypothesis) adaptive logrank test with alpha=0.05 (except R3: alpha=0.025) and power=0.80. For all risk groups R1, R2loc,R2pulm and R3 three interim analyses are intended to be performed using an inverse normal design corresponding to an equally spaced four step group sequential design according to O’Brien & Fleming (Wassmer 2006, O’Brien & Fleming 1979). After each interim analysis a data dependent sample size calculation may be performed. Then, the accrual period, the observation time and the schedule of the next interim and final analysis (required number of events) can be adapted. If no adaptions are performed, the inverse normal design coincides with the underlying group sequential design. The Schoenfeld formula was used to compute the necessary number of events (Schoenfeld, 1981). Sample size calculations were computed with Addplan Software V. 3.1.3 and ADDPLAN V. 6.0 (Wassmer, 2006).

Recruitment

Recruitment status

Active, not recruiting

Date of first participant enrolment

Anticipated

Actual

27/08/2014

Date of last participant enrolment

Anticipated

31/12/2018

Actual

31/03/2018

Date of last data collection

Anticipated

31/12/2023

Actual

Sample size

Target

1383

Accrual to date

Final

1330

Recruitment in Australia

Recruitment state(s)

NSW,QLD,WA,VIC

Recruitment hospital [1]

The Chris O’Brien Lifehouse - Camperdown

Recruitment hospital [2]

Peter MacCallum Cancer Centre - Melbourne

Recruitment hospital [3]

Monash Medical Centre - Clayton campus - Clayton

Recruitment hospital [4]

The Royal Childrens Hospital - Parkville

Recruitment hospital [5]

Princess Margaret Hospital - Subiaco

Recruitment hospital [6]

Westmead Private Hospital - Westmead

Recruitment hospital [7]

Lady Cilento Children's Hospital - South Brisbane

Recruitment postcode(s) [1]

2050 - Camperdown

Recruitment postcode(s) [2]

3000 - Melbourne

Recruitment postcode(s) [3]

3168 - Clayton

Recruitment postcode(s) [4]

3052 - Parkville

Recruitment postcode(s) [5]

6008 - Subiaco

Recruitment postcode(s) [6]

2145 - Westmead

Recruitment postcode(s) [7]

4101 - South Brisbane

Recruitment outside Australia

Country [1]

Austria

State/province [1]

Wien

Country [2]

Belgium

State/province [2]

Brussels

Country [3]

Czech Republic

State/province [3]

Prague

Country [4]

Finland

State/province [4]

Helsinki

Country [5]

Germany

State/province [5]

Munster

Country [6]

Hungary

State/province [6]

Budapest

Country [7]

Lithuania

State/province [7]

Vilnius

Country [8]

Netherlands

State/province [8]

Amsterdam

Country [9]

Poland

State/province [9]

Warzawa

Country [10]

Slovenia

State/province [10]

Ljubljana

Country [11]

Sweden

State/province [11]

Lund

Country [12]

Swaziland

State/province [12]

Bern

Country [13]

France

State/province [13]

lyon

Country [14]

United Kingdom

State/province [14]

Manchester

Country [15]

United States of America

State/province [15]

Seattle

Country [16]

New Zealand

State/province [16]

New Zealand

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

Rainbows for Kate

Country [1]

Australia

Primary sponsor type

University

Name

University Clinic in Essen

Country

Australia

Secondary sponsor category [1]

Other Collaborative groups

Name [1]

Australasian Sarcoma Study Group

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Monash Health HREC

Ethics committee address [1]

Monash Health
Monash Medical Centre
246 Clayton Road,
Clayton
VIC   3168
Australia

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

07/02/2014

Approval date [1]

07/03/2014

Ethics approval number [1]

13428B

Ethics committee name [2]

Royal Prince Alfred Hospital Ethics Committee

Ethics committee address [2]

Research Development Office
Royal Prince Alfred Hospital
Missenden Rd, Camperdown NSW 2050

Ethics committee country [2]

Australia

Date submitted for ethics approval [2]

Approval date [2]

13/10/2014

Ethics approval number [2]

X14-0195 / LH15.056

Ethics committee name [3]

Princess Margaret Hospital Human Research Ethics Committee

Ethics committee address [3]

Princess Margaret Hospital
Human Research Ethics Commitee
Roberts Road
Subiaco
WA,    6008

Ethics committee country [3]

Australia

Date submitted for ethics approval [3]

Approval date [3]

23/07/2014

Ethics approval number [3]

2014041EP

Summary

Brief summary

What is this project about?	
EWING 2008 is a joint protocol of European and North American Ewing sarcoma study groups. The protocol is aimed at optimising treatment and treatment results of patients with Ewing sarcomas. 
Who is it for?
The EWING 2008 protocol is open to all patients aged 4-49 years, diagnosed with Ewing sarcomas of bone or soft tissue, localised or metastatic, who are considered eligible for neoadjuvant chemotherapy. 
Study details
All patients registered will receive induction chemotherapy consisting of six cycles of vincristine, ifosfamide, doxorubicin and etoposide (VIDE). The decision regarding local therapy must be made following the fifth cycle of induction treatment, with a preference for surgical intervention with or without additional radiotherapy. Standard Risk R1 Good responders (R1) (< 10% viable tumour cells) with localised disease are allocated to the standard risk arm and will receive a further eight cycles of chemotherapy composed of vincristine, actinomycin D, and cyclophosphamide (VAC) (females) or ifosfamide instead of cyclophosphamide (VAI) (males). They will be randomised to receive add-on treatment with zoledronic acid, or no add-on treatment.  Very High Risk R3 Patients with disseminated disease, i.e. dissemination to bone and/or other sites and possibly additional pulmonary dissemination (R3), receive six cycles of VIDE induction chemotherapy. Patients are then randomised to either continue with eight cycles of vincristine, actinomycin D and cyclophosphamide (VAC) chemotherapy or high dose treosulfan-melphalan (TreoMel) chemotherapy followed by autologous stem cell reinfusion followed thereafter by eight cycles of VAC chemotherapy. Local therapy in R3 patients is following VIDE induction, whenever feasible prior to high dose therapy (HDT).
It is hoped that the findings from this trial will provide information of the efficacy and toxicity of each of the chemotherapy treatment protocols for patients newly diagnosed with Ewing sarcoma.

Trial website

Public notes

High Risk R2loc arm and the R2pulm arm patients were reclassified as registry patients as of December 1st 2015. The study committee decided to discontinue accrual as of 1.12.2015 due to declining recruitment rates (accrual for randomization until 30.11.2015)

Contacts

Principal investigator

Name

Prof Uta Dirksen

Address

Universitätsklinikum Essen
Zentrum für Kinder- und Jugendmedizin
Kinderheilkunde III
EWING 2008 Studie
Hufelandstraße 55
45147 Essen
Deutschland
Germany

Country

Germany

Phone

+49 201 723 8084

Email

uta.dirksen@uk-essen.de

Contact person for public queries

Name

Christine Russell

Address

Peter MacCallum Cancer Centre
305 Grattan Street,
Melbourne, 3000
VIC
Australia

Country

Australia

Phone

+61 3 8559 7527

Email

christine.russell@petermac.org

Contact person for scientific queries

Name

Vivek Bhadri

Address

VMO Medical Oncology
119-143 Missenden Road
Camperdown
NSW 2050
Australia

Country

Australia

Phone

+61 2 8514 0749

Email

vivek.bhadri@lh.org.au

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